The unifying theme of this application is the incidence of multiple chronic conditions (MCC) and its mechanisms and health outcomes. In the United States, about 62% of Medicare recipients ages 65 to 74 years have MCC (= 2 chronic conditions), and the frequency increases dramatically to 82% above age 85. Because adults with MCC are at increased risk of functional decline and are particularly vulnerable to poor care, MCC threatens both the public and financial health of the United States. MCC prevalence may be reduced by delaying the onset of single conditions and combinations of conditions through modification of risk factors or determinants of diseases. However, current preventive efforts have partly failed because they have focused on one disease at a time and too late in life. For this reason, there is a critical need to identify groups of individuals at risk earlier in life, an to develop interventions to prevent MCC and its adverse health outcomes. These priorities were outlined in the Multiple Chronic Conditions Strategic Framework of the US Department of Health and Human Services (DHHS) of 2010. The DHHS also developed a list of 20 conditions considered a public health priority for the nation. Although data are available about the prevalence of MCC in the United States and worldwide, the incidence of MCC and its epidemiologic mechanisms and health outcomes remain poorly understood. The Rochester Epidemiology Project (REP) is an ideal environment to study the incidence of MCC because it includes information for all ages from newborns to death, regardless of insurance status or health care setting (both inpatient and outpatient care), and encompasses the full spectrum of care, from primary to tertiary care. In this renewal application, we propose to study the mechanisms of development of incident MCC for specific physical and mental health conditions across all ages (Aim 1), and to identify short-term and long-term health outcomes of incident MCC dyads (Aim 2). This knowledge will inform earlier and more integrated interventions to prevent MCC and to improve its outcomes at the local community level and at the national level, as recommended by the DHHS and other federal agencies. Finally, we will develop an innovative approach to share REP data and our MCC findings to inform research and practice (Aim 3). Broad sharing of the comprehensive and longitudinal REP data both locally and to the wider scientific, clinical, and public health community will allow investigators and practitioners worldwide to rapidly explore patterns of diseases, procedures, drug prescriptions, MCC, and their associations at no cost. In summary, the studies proposed here are novel, can be efficiently conducted using the REP, and are urgently needed.